Figure 4. Both mature and immature hAPP-expressing OSNs showed reduced survival but were differentially rescued by turning off hAPP transgene. a, Experimental timeline shows all BrdU injections in 2-week-old animals and olfactory tissue harvested 2 h, 7 d, or 14 d later. Images show OE immunostained for BrdU (white dots) corresponding to time points above. b, Quantification of BrdU-positive cells at 2 week (+2 h) point showed a significantly greater number in Gγ8-hAPP line (107 ± 18, n = 5) than either OMP-hAPP (59 ± 6, n = 3) or tetO-hAPP controls (52 ± 3, n = 4) (black asterisk), revealing increased proliferation in Gγ8-hAPP line. A significant drop in BrdU-positive cells in 3-week-old Gγ8-hAPP mice (22 ± 7, n = 4) compared with that in 2-week-old Gγ8-hAPP mice (red asterisks), as well as 3-week-old OMP-hAPP (69 ± 15, n = 4) and tetO-hAPP (65 ± 21, n = 5) (black asterisk) identified a susceptibility period of apoptosis in immature OSNs. In OMP-hAPP mice, a similar significant drop occurred between 3 and 4 weeks of age (4w: 9 ± 4, n = 4; green asterisk), revealing a later susceptibility period in mature neurons. Both mutant lines had significantly fewer BrdU-positive neurons at 4 weeks of age (Gγ8-hAPP: 8 ± 1, n = 3) than tetO-hAPP (43 ± 16, n = 4) (black asterisk). c, Timeline of recovery experiments shows BrdU injections in 2-week-old mice, followed by Dox-chow (which turns off hAPP expression) given to Gγ8-hAPP mice from 2 to 3 weeks of age, and OMP-hAPP mice from 3 to 4 weeks of age (see Materials and Methods), based upon the susceptibility periods for each line determined above. d, OE from Dox-treated mice described in c, showing rapid recovery in Gγ8-hAPP line and delayed recovery in OMP-hAPP line. Graphs show significant changes in Dox-treated compared with nontreated Gγ8-hAPP OE, including increased BrdU-positive cells (Dox, 67 ± 14, n = 3; no-Dox, 22 ± 7, n = 4); decreased caspase3-positive cells (Dox, 4 ± 1, n = 3; no-Dox, 9 ± 2, n = 4) and increased OMP-positive cells (Dox, 383 ± 62, n = 3; no-Dox, 177 ± 41, n = 4). Dox-treated OMP-hAPP mice showed smaller changes compared with nontreated in BrdU-positive cells (Dox, 13 ± 5, n = 3; no-Dox, 9 ± 4, n = 4), caspase3-positive cells (Dox, 7 ± 3, n = 3; no-Dox, 8 ± 2, n = 8) and OMP-positive cells (Dox, 296 ± 22, n = 3; no-Dox, 230 ± 26, n = 5). Significance: *p < 0.05; **p < 0.001. Scale bar, 50 μm.